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Phosphoglycerate kinase acts in tumour angiogenesis as a disulphide reductase

Abstract

Disulphide bonds in secreted proteins are considered to be inert because of the oxidizing nature of the extracellular milieu. An exception to this rule is a reductase secreted by tumour cells that reduces disulphide bonds in the serine proteinase plasmin1,2. Reduction of plasmin initiates proteolytic cleavage in the kringle 5 domain and release of the tumour blood vessel inhibitor angiostatin3. New blood vessel formation or angiogenesis is critical for tumour expansion and metastasis4,5. Here we show that the plasmin reductase isolated from conditioned medium of fibrosarcoma cells is the glycolytic enzyme phosphoglycerate kinase6. Recombinant phosphoglycerate kinase had the same specific activity as the fibrosarcoma-derived protein. Plasma of mice bearing fibrosarcoma tumours contained several-fold more phosphoglycerate kinase, as compared with mice without tumours. Administration of phosphoglycerate kinase to tumour-bearing mice caused an increase in plasma levels of angiostatin, and a decrease in tumour vascularity and rate of tumour growth. Our findings indicate that phosphoglycerate kinase not only functions in glycolysis but is secreted by tumour cells and participates in the angiogenic process as a disulphide reductase.

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Figure 1: Assay and purification of plasmin reductase.
Figure 2: Recombinant human PGK has plasmin reductase activity.
Figure 3: PGK is secreted by cultured tumour cells.
Figure 4: PGK is secreted by tumours, and administration of PGK to tumour-bearing mice causes an increase in plasma levels of angiostatin that contains free thiols.
Figure 5: Administration of PGK to tumour-bearing mice results in decrease in tumour vascularity and rate of tumour growth.

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Acknowledgements

This work was supported by the National Health and Medical Research Council of Australia, the National Heart Foundation of Australia, the New South Wales Cancer Council and the NIH, USA. The authors gratefully acknowledge the support of J. Folkman, in whose laboratory the animal experiments were conducted, and thank D. Prox and C. Becker for technical assistance.

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Correspondence to Philip J. Hogg.

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Lay, A., Jiang, XM., Kisker, O. et al. Phosphoglycerate kinase acts in tumour angiogenesis as a disulphide reductase . Nature 408, 869–873 (2000). https://doi.org/10.1038/35048596

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